MECHANISMS OF CUTANEOUS ACTIVE VASODILATION IN HUMANS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project will determine the identity and functional significance of transmitters from sympathetic vasoconstrictor and vasodilator controls in the human cutaneous circulation. OBJECTIVES: To clarify the mechanisms by which the cutaneous active vasodilator system works. The general hypothesis to be tested by this project is that active thermoregulatory vasodilation in the human cutaneous circulation is mediated by a cholinergic co-transmitter system involving acetylcholine and neuropeptides. SPECIFIC AIMS: 1) determine whether bradykinin is involved in cutaneous active vasodilation during heat stress; 2) clarify whether nitric oxide levels increase and cause cutaneous active vasodilation during heat stress or whether the level of nitric oxide remains constant and functions as a permissive factor during heat stress; 3) determine whether the nitric oxide required for cutaneous active vasodilation during heat stress is produced by endothelial nitric oxide synthase (eNOS) or by neuronal nitric oxide synthase (nNOS); 4) Determine the role of vasoactive intestinal polypeptide (VIP) in cutaneous active vasodilation during heat stress; 5) determine the role of cAMP in cutaneous active vasodilation during heat stress; 6) determine the role of cGMP in cutaneous active vasodilation during heat stress; and 7) determine the degree of dependence of cutaneous vasodilation on cholinergic transmission in cystic fibrosis. RESEARCH PLAN: The foregoing specific aims will be addressed by application of a novel combination of techniques: intradermal microdialysis and laser-Doppler Flowmetry (LDF). Protocols will be conducted in humans. Intradermal microdialysis will be used to deliver pharmacological agents into the skin. Bioavailable NO concentrations will be measured by NO-selective, amphometric electrodes. Blood flow at microdialysis sites will be simultaneously measured by LDF. Measurements will be made during basal (normothermia) and stimulated (whole body heating) activity of the active vasodilator system. By comparing the responses between basal and stimulated activity and between control (untreated) and experimental (drug treated) microdialysis sites, the mechanisms of active vasodilation will be elucidated. METHODS: 1) Intra-dermal electrodes will serve to measure interstitial bioavailable NO levels from the cutaneous interstitial space. 2) Intra-dermal microdialysis will serve to deliver drugs into the interstitial space. 3) Laser-Doppler Flowmetry will be used to measure blood flow responses to pharmacological manipulation of vasodilator mechanisms during normothermia and whole body heating. 4) A water perfused suit (covers the entire body except for arms, feet, and head) will be used to effect whole body cooling, normothermia, or hyperthermia by perfusing with cold, neutral, or warm water respectively. 5) Local temperature control of measurement sites will be accomplished with resistive heaters. 6) Sweat rate is measured with relative humidity monitors placed on the skin surface. CLINICAL RELEVANCE: The specific mechanisms whereby the sympathetic nervous system causes increases in skin blood flow during hyperthermia remain enigmatic. The proposed experiments address fundamental questions about the nature of these mechanisms in humans. These studies should clarify the mechanistic rationale for use of alternative therapies to treat cardiovascular disorders in persons potentially at risk for heat related disorders. In addition, elderly populations have a greater incidence of heat related deaths. Among Veterans, the percentage of elderly is twice that of the U.S. population. This project will provide knowledge relevant to a significant number of veterans.